title: Confirmation of ALDH2 as a Major locus of drinking behavior and of its variants regulating multiple metabolic phenotypes in a Japanese population.
abstract: BACKGROUND
  Normative alcohol use (or drinking behavior) influences the risk of cardiovascular disease in a multi-faceted manner. To identify susceptibility gene variants for drinking behavior, a 2-staged genome-wide association study was performed in a Japanese population.
  
  
  RESULTS
  In the stage-1 scan, 733 cases and 729 controls were genotyped with 456,827 SNP markers. The associated loci without redundancy of linkage disequilibrium were further examined in the stage-2 general population panel comprising 2,794 drinkers (≥ once per week), 1,521 chance drinkers (< once per week), and 1,351 non-drinkers. Along with genome-wide exploration, we aimed to replicate the trait association of a candidate gene SNP previously reported (rs1229984 in ADH1B). A cluster of 12 SNPs on 12q24 were found to significantly (P<5×10(-8)) associate with drinking behavior in stage 1, among which rs671 (a Glu-to-Lys substitution at position 504) in the ALDH2 gene showed the strongest association (odds ratio (OR)=0.16, P=3.6×10(-211) in the joint analysis). The association was also replicated for rs1229984 (OR=1.20, P<3.6×10(-4)). Furthermore, ALDH2 504Lys was associated with several metabolic traits, eg, lower levels of high-density lipoprotein cholesterol and liver enzymes-AST, ALT, and γGTP-by interacting with alcohol intake.
  
  
  CONCLUSIONS
  Our results confirm ALDH2 as a major locus regulating drinking behavior in the Japanese, indicating that the ALDH2 504Lys variant exerts pleiotropic effects on risk factors of cardiovascular disease among drinkers.
authors.affiliation: Department of Gene Diagnostics and Therapeutics, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Takeuchi
authors.forename: Masato
authors.initials: M
authors.lastname: Isono
authors.forename: Toru
authors.initials: T
authors.lastname: Nabika
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Katsuya
authors.forename: Takao
authors.initials: T
authors.lastname: Sugiyama
authors.forename: Shuhei
authors.initials: S
authors.lastname: Yamaguchi
authors.forename: Shotai
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Toshio
authors.initials: T
authors.lastname: Ogihara
authors.forename: Yukio
authors.initials: Y
authors.lastname: Yamori
authors.forename: Akihiro
authors.initials: A
authors.lastname: Fujioka
authors.forename: Norihiro
authors.initials: N
authors.lastname: Kato
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000444:Aldehyde Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D019943:Amino Acid Substitution; D044466:Asian People; D002318:Cardiovascular Diseases / Q000201:enzymology / Q000235:genetics*; D004327:Drinking Behavior; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
chemical_list: C096127:ALDH2 protein, human; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial